We propose to acquire a state-of-the-art high field, wide-bore, solid-state NMR spectrometer for studies of membrane proteins, fibrils and other non-crystalline or microcrystalline solids. The instrument will be equipped for multidimensional magic-angle spinning experiments, to resolve and assign 1H, 13C, and 15N signals throughout peptides and proteins with molecular masses from 5 to at least 150 kDa. The instrument will permit analysis of long-range distances and dynamics with 19F, 31P and 2H nuclei, and be customized for the purpose of implementing experiments that have been previously demonstrated for total structure determination. Novel capabilities of the proposed instrument include enhanced sensitivity and resolution, improved operational stability for 3D and 4D experiments with long acquisition times, extended low temperature operation, quadruple resonance and fast (>40 kHz) magic-angle spinning. The instrument will support ongoing collaborative projects among investigators at the University of Illinois at Urbana-Champaign to solve structures of proteins involved in neurodegenerative, cardiovascular, and infectious diseases. Samples in these studies are prepared as non-crystalline solids in native membranes, in synthetic membranes, as fibrous aggregates, or as microcrystalline precipitates; the samples lack long-range order and are insoluble, and therefore are not amenable to X-ray crystallography or solution NMR spectroscopy. The PI has developed new solid- state NMR methods including 3D techniques for high-resolution structure determination with dipole tensor refinement, the first 4D chemical shift assignment methods for solid proteins, and techniques for sensitivity enhancement with proton detection. Using the proposed instrument, these techniques will be applied to solve structures of membrane and fibrous proteins for which sample preparation methods and preliminary spectra are available. PUBLIC HEALTH RELEVANCE: The proposed instrument will enable structure determination of proteins implicated in Parkinson's disease, diabetes, blood clotting, drug metabolism and HIV/AIDS. Many of these proteins are natively found in membrane or fibrous forms that are not readily studied using other methods. The SSNMR-determined structures will benefit fundamental understanding of disease etiology and provide targets for the design of more effective drug therapies. [unreadable] [unreadable] [unreadable]